The present invention relates to certain novel A3 adenosine receptor antagonists, pharmaceutical compositions, and methods of selectively blocking A3 adenosine receptors in a mammal. The present invention also relates to methods of preventing or treating various medical disorders or conditions with the adenosine receptor antagonists.
The use of caffeine and other alkylxanthines as physiological stimulants is well known. The principle mechanism by which caffeine and other alkylxanthines act as physiological stimulants is by blocking the effects of the ubiquitous neuromodulator adenosine. Daly, xe2x80x9cMechanism of Action of Caffeinexe2x80x9d, in Caffeine, Coffee and Health, (S. Garattini, Ed.), Chapter 4, pp. 97-150 (1993). Adenosine is produced locally in response to increased activity or stress to the system. This feedback mechanism allows the organ to compensate for the stress by decreasing energy demand (depressant activity) and increasing oxygen supply (e.g., by vasodilation). Bruns, Nucleosides and Nucleotides, 10, 931-944 (1991).
Adenosine plays several key physiological roles. In addition to its role in intermediary metabolism, adenosine displays a number of receptor-mediated physiological actions, including dilation of coronary vessels, inhibition of platelet aggregation, and inhibition of lipolysis. Bruns et al., Proc. Nat. Acad. Sci. U.S.A., 77, 5547-5551 (1980). Adenosine receptors, A1, A2, and A3, belong to the G protein-coupled superfamily characterized by seven transmembrane helical domains. Several antagonists have been reported for these receptors in the literature. See, for example, Jacobson et al., xe2x80x9cDevelopment Of Selective Purinoceptor Agonists And Antagonistsxe2x80x9d, in Purinergic Approaches In Experimental Therapeutics, K. A. Jacobson and M. F. Jarvis, Ed, Wiley, Ch. 6, pp. 101-128 (1997). The pharmacology of the A3 receptor is unique within the class of adenosine receptors. Zhou et al., Proc. Natl. Acad. Sci. USA, 89, 7432-7436 (1992).
The distribution of the A3 receptor is found primarily in the central nervous system (CNS), brain, testes, and immune system, where it appears to be involved in the modulation of release from mast cells of mediators of the immediate hypersensitivity reaction. Ramkumar et al., J. Biol. Chem., 268, 16887-16890 (1993). It is believed that A3-selective compounds will have utility in the therapeutic and/or prophylactic treatment of cardiac disease, infertility, kidney disease, and CNS disorders. Activation of the A3 receptor has been linked to several second messenger systems such as stimulation of phospholipidases C and D and inhibition of adenylyl cyclase. Ali et al., J. Pharmacol. Exp. Therap., 276, 837-845 (1996).
Antagonists for the A3 receptor are sought as potential anti-inflammatory, antiasthmatic, and antiischemic agents. von Lubitz et al., Eur. J. Pharmacol., 263, 59-67 (1994); Soc. For Neurosciences, Abstr. 745.16, 23, 1924 (1997). Some promising leads for A3 adenosine receptor antagonists have been identified in certain 1,4-dihydropyridines, triazoloquinazolines, flavonoids, a triazolonaphthyridine, and a thiazolopyrimidine. Van Rhee et al., J. Med. Chem., 39, 2980-2989 (1996); Jiang et al., J. Med. Chem., 39, 4667-4675 (1996); Jiang et al., J. Med. Chem., 40, 2596-2608 (1997); Kim et al., J. Med. Chem., 39, 4142-4148 (1996); Karton et al., J. Med. Chem., 39, 2293-2301 (1996); Jacobson et al., Drug Devel. Res., 37, 131 (1996). WO 97/27177 discloses certain dihydropyrdines, pyridines, flavonoids, and triazoloquinazolines as possible A3 adenosine receptor antagonists. Li et al., J. Med. Chem., 41, 3186-3201 (1998) discloses certain pyridine derivatives as possible A3 adenosine receptor antagonists.
Thus, there remains a need for antagonists for A3 adenosine receptors. The present invention seeks to provide such compounds, as well as methods of using these compounds to selectively block adenosine receptors in mammals, and pharmaceutical compositions comprising such compounds. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides compounds of formula (I) 
wherein R2 is selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, and C1-C6 alkoxy C1-C6 alkyl; R3 is selected from the group consisting of C1-C6 alkoxy, C1-C6 alkylsulfanyl, hydroxy, C1-C6 alkoxy C1-C6 alkylsulfanyl, hydroxy C1-C6 alkylsulfanyl, and halo C1-C6 alkylsulfanyl, or R3 together with R4 forms a 3-7 membered heterocyclic ring containing O, N, or S; R4 is selected from the group consisting of C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, C1-C6 alkoxy, C1-C6alkylsulfanyl, C1-C6 alkylamino, C1-C6 alkylcarbonyl sulfanyl C1-C6 alkyl, aryl C2-C6 alkenyl, aryl C2-C6 alkynyl, formyl, and acetal; R5 is selected from the group consisting of C1-C6 alkyl, aryl C1-C6 alkyl, hydroxy C1-C6 alkyl, and halo C1-C6 alkyl; and R6 is selected from the group consisting of aryl, C3-C7 cycloalkyl, and haloaryl; wherein the aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
The present invention further provides compounds of formula (II) 
wherein R2 is a C1-C6 alkyl; R3 is selected from the group consisting of C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkylsulfanyl, and C1-C6 alkylsulfanyl; R4 is selected from the group consisting of C1-C6 alkyl, acetal, formyl, aryl C2-C6 alkenyl, and aryl C2-C6 alkynyl; R5 is selected from the group consisting of C1-C6 alkyl and aryl C1-C6 alkyl; and R6 is selected from the group consisting of aryl and C3-C6 cycloalkyl; wherein said aryl is a phenyl or naphthyl; or a pharmaceutically acceptable salt thereof.
The present invention further provides pharmaceutical compositions comprising any of the aforesaid compounds and a method of treating a mammal comprising selectively blocking one or more of the adenosine receptors, particularly the A3 adenosine receptors, of the mammal by administering to the mammal at least one compound of formulas I and II.
The present invention further provides a method of characterizing an adenosine receptor, particularly an A3 receptor, in a substrate comprising contacting said substrate with a compound of the present invention and evaluating the interaction of the compound with the adenosine receptor.
The present invention further provides a method of inhibiting the binding of a ligand to an adenosine receptor, particularly an A3 receptor, of a substrate comprising contacting the substrate with a compound of the present invention so that the compound binds to the adenosine receptor and inhibits the ligand from binding to the adenosine receptor.